A large body of evidence from many different model systems strongly supports the hypothesis that learning and memory are due to cellular changes occurring within individual neurons. While the strength of neuronal connections is dynamic, structural connectivity in normal adult brains is generally thought to be stable. Data from a number of different model systems, however, indicate that the structure of individual neurons is modified by learning. The goal of this project is to use the marine mollusk Aplysia as a model system to understand the role of morphological changes in learning and to characterize the cellular mechanisms underlying these modifications. Two specific aims will be addressed in this project. First, we will investigate the role that modifications of neuronal structure play in learning. We recently found that changes in sensory neuron structure were not correlated with a relatively transient form of long-term sensitization. Our new hypothesis is that structural changes are only induced when a persistent form of long-term sensitization is induced. We plan to test this hypothesis by: 1) undertaking a thorough behavioral analysis of long- term sensitization; 2) developing a more complete understanding of the conditions required to induce morphological changes; and 3) investigating the functional role that changes in neuronal structure play in behavioral modifications. In addition, the possibility that structural changes produced by training are due to axon injury will be investigated. Second, we will investigate the role of growth factors in modification of neuronal structure. Our hypothesis is that the metalloprotease apTBL-1 regulates neuronal growth by activating TGFBeta. This hypothesis will be tested by: 1) examining the distribution of apTBL-1 throughout the nervous system and within neurons that express the protein; and 2) examining the effects of TGFBeta on neuronal morphology using an in vitro analogue of long-term sensitization. This system will allow us to use macromolecules such as antibodies to examine the functional relationships among 5-HT, apTBL-1 and TGFBeta and their regulation of synaptic strength and neuronal structure.